Alveolar epithelium has been shown to be damaged by exposure to a variety of airborne toxic substances. Following a repair mechanism that involves hyperplasia of Type II cells with subsequent transformation to Type I cells, the newly formed epithelium appears to be more tolerant to the damaging effects of oxidants. However, previous reports indicate that during the cell proliferative stage of repair the epithelium is more susceptible to oxidant exposures that can lead to the development of irreversible fibrotic lesions. The project hypothesis is that although newly formed cells might have increased metabolic capabilities, dividing cells have insufficient reserve metabolic capabilities to deal with the added demands associated with oxidant exposures. This study will establish reversible and irreversible models of epithelial injury by using different inhalation exposures of rats to ozone (0.5-1.5ppm). The ability of the lung to maintain such homeostatic processes as energy generation and cellular antioxidant defense mechanisms, will be assessed in intact perfused lungs isolated from animals during the first 24h of exposure, during epithelial hyperplasia, and following completion of repair. These metabolic processes will be indicated by measurements of lung glycolytic, mitochondrial and pentose cycle activities, and by its ability to maintain reduced glutathione levels on metabolism of t-butylhydroperoxide and to synthesize the surfactant lipid dipalmitoylphosphatidylcholine. The biochemical basis of susceptibility and tolerance to the damaging effects of oxidants at different stages of epithelial damage and repair will be established by correlation of changes in morphology with measurements of the lung's reserve capacity to maintain homeostasis. Such reserves will be determined by evaluating maximal metabolic fluxes, brought about by artificially stimulating the utilization of ATP and reducing equivalents (NADPH) with the uncoupler of oxidative phosphorylation 2,4-dinitrophenol, and with the electron acceptor phenazine methosulphate, respectively. These studies will contribute to a better understanding of how biochemical events can influence the development of irreversible diseases associated with the inhalation of toxic substances found in urban and workplace environments.